Open AccessRegional metabolic heterogeneity of the hippocampus is nonuniformly impacted by age and caloric restriction
Author(s) -
Martin Stephen A.,
DeMuth Tyler M.,
Miller Karl N.,
Pugh Thomas D.,
Polewski Michael A.,
Colman Ricki J.,
Eliceiri Kevin W.,
Beasley Timothy Mark,
Johnson Sterling C.,
Anderson Rozalyn M.
Publication year - 2016
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12418
Subject(s) - biology , hippocampal formation , hippocampus , medicine , endocrinology , cytochrome c oxidase , calorie restriction , nad+ kinase , regulator , mitochondrion , biochemistry , enzyme , gene
Summary The hippocampus is critical for cognition and memory formation and is vulnerable to age‐related atrophy and loss of function. These phenotypes are attenuated by caloric restriction ( CR ), a dietary intervention that delays aging. Here, we show significant regional effects in hippocampal energy metabolism that are responsive to age and CR , implicating metabolic pathways in neuronal protection. In situ mitochondrial cytochrome c oxidase activity was region specific and lower in aged mice, and the impact of age was region specific. Multiphoton laser scanning microscopy revealed region‐ and age‐specific differences in nicotinamide adenine dinucleotide ( NAD )‐derived metabolic cofactors. Age‐related changes in metabolic parameters were temporally separated, with early and late events in the metabolic response to age. There was a significant regional impact of age to lower levels of PGC ‐1α, a master mitochondrial regulator. Rather than reversing the impact of age, CR induced a distinct metabolic state with decreased cytochrome c oxidase activity and increased levels of NAD (P)H. Levels of hippocampal PGC ‐1α were lower with CR , as were levels of GSK 3β, a key regulator of PGC ‐1α turnover and activity. Regional distribution and colocalization of PGC ‐1α and GSK 3β in mouse hippocampus was similar in monkeys. Furthermore, the impact of CR to lower levels of both PGC ‐1α and GSK 3β was also conserved. The studies presented here establish the hippocampus as a highly varied metabolic environment, reveal cell‐type and regional specificity in the metabolic response to age and delayed aging by CR , and suggest that PGC ‐1α and GSK 3β play a role in implementing the neuroprotective program induced by CR .